scholarly journals Differential Flap Dynamics in Wild-Type and a Drug Resistant Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation

2012 ◽  
Vol 8 (10) ◽  
pp. 3452-3462 ◽  
Author(s):  
Yufeng Cai ◽  
Nese Kurt Yilmaz ◽  
Wazo Myint ◽  
Rieko Ishima ◽  
Celia A. Schiffer
Keyword(s):  
Molecular Dynamics ◽  
Nmr Relaxation ◽  
Drug Resistant ◽  
Wild Type ◽  
Resistant Variant ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Backbone 1H, 13C, and 15N chemical shift assignment for HIV-1 protease subtypes and multi-drug resistant variant MDR 769

2012 ◽  
Vol 7 (2) ◽  
pp. 199-202 ◽  
Author(s):  
Xi Huang ◽  
Ian Mitchelle S. de Vera ◽  
Angelo M. Veloro ◽  
James R. Rocca ◽  
Carlos Simmerling ◽  
...  
Keyword(s):  
Chemical Shift ◽  
Chemical Shift Assignment ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Shift Assignment ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Extreme Entropy–Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease

2012 ◽  
Vol 7 (9) ◽  
pp. 1536-1546 ◽  
Author(s):  
Nancy M. King ◽  
Moses Prabu-Jeyabalan ◽  
Rajintha M. Bandaranayake ◽  
Madhavi N. L. Nalam ◽  
Ellen A. Nalivaika ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Resistant Variant ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Defective Hydrophobic Sliding Mechanism and Active Site Expansion in HIV-1 Protease Drug Resistant Variant Gly48Thr/Leu89Met: Mechanisms for the Loss of Saquinavir Binding Potency

Biochemistry ◽  
2015 ◽  
Vol 54 (2) ◽  
pp. 422-433 ◽  
Author(s):  
Nathan E. Goldfarb ◽  
Meray Ohanessian ◽  
Shyamasri Biswas ◽  
T. Dwight McGee ◽  
Brian P. Mahon ◽  
...  
Keyword(s):  
Active Site ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Sliding Mechanism ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Molecular Dynamics Studies of the Inhibitor C34 Binding to the Wild-Type and Mutant HIV-1 gp41: Inhibitory and Drug Resistant Mechanism

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e111923 ◽  
Author(s):  
Xueting Ma ◽  
Jianjun Tan ◽  
Min Su ◽  
Chunhua Li ◽  
Xiaoyi Zhang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistant ◽  
Wild Type ◽  
Hiv 1

scholarly journals Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 78 (4) ◽  
pp. 1718-1729 ◽  
Author(s):  
Haili Zhang ◽  
Yan Zhou ◽  
Cecily Alcock ◽  
Tara Kiefer ◽  
Daphne Monie ◽  
...  
Keyword(s):  
Drug Combination ◽  
Wild Type Virus ◽  
Replication Capacity ◽  
Drug Resistant ◽  
Type Virus ◽  
Wild Type ◽  
Cell Level ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.

Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus

AIDS ◽  
2003 ◽  
Vol 17 (7) ◽  
pp. F11-F16 ◽  
Author(s):  
Kersten K Koelsch ◽  
Davey M Smith ◽  
Susan J Little ◽  
Caroline C Ignacio ◽  
Theresa R Macaranas ◽  
...  
Keyword(s):  
Primary Infection ◽  
Wild Type Virus ◽  
Drug Resistant ◽  
Type Virus ◽  
Wild Type ◽  
Clade B ◽  
B Virus ◽  
Hiv 1

scholarly journals High Potency of Indolyl Aryl Sulfone Nonnucleoside Inhibitors towards Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutants Is Due to Selective Targeting of Different Mechanistic Forms of the Enzyme

2005 ◽  
Vol 49 (11) ◽  
pp. 4546-4554 ◽  
Author(s):  
Reynel Cancio ◽  
Romano Silvestri ◽  
Rino Ragno ◽  
Marino Artico ◽  
Gabriella De Martino ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mechanism Of Action ◽  
Drug Resistant ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.

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